The invention relates to a process for carbonxe2x80x94carbon bond formation starting from chloro- or fluoroaromatics by reacting with lithium metal and a carbon electrophile, whereby a wide gamut of alkyl- or aryl-substituted aromatics and heteroaromatics may be obtained. 
This type of conversion of chloro- and fluoroaromatics to alkyl- and aryl-substituted aromatics and heteroaromatics provides, for example, a very wide gamut of versatile intermediates and active ingredients for the agrochemical and pharmaceutical industry that are of great economic interest.
Many different routes for the conversion of haloaromatics to alkyl- or aryl-substituted aromatics are described in numerous publications, and for many of these reactions there are general procedures whereby even the target compounds in each case can be obtained in good yields.
The most important and very widely applicable general procedure is the conversion of haloaromatics to Grignard compounds, which can subsequently be reacted with a wide gamut of carbon electrophiles to give the target compounds. The reaction of bromo- or iodoaromatics to give Grignard compounds succeeds in the absence of traces in the haloaromatic which react with the Grignard functionality in almost all cases in good to very good yields. However, it must be taken into account that bromo- and iodoaromatics are almost always significantly more expensive than the corresponding chloroaromatics, so that it is obligatory to use the latter to obtain competitive industrial preparative processes. Unfortunately there are numerous cases in which, starting from the corresponding chloro- or fluoroaromatics, the Grignard compounds can only be obtained in poor yields, using specialized, often expensive solvents or using expensive activation methods for the magnesium metal. For example, this applies to 1-chloronaphthalene, which requires the use of Rieke magnesium, an example of a specialized and expensive technique, in order to achieve any worthwhile yields.
In these cases, there are hardly any alternatives to the use of the bromo- or iodoaromatics, since metallation using e.g. butyllithium does not work with chloroaromatics, and the reverse procedure, e.g. coupling of the haloaromatic with a nucleophilic reagent, such as an alkyl or aryl Grignard or a boronic acid, usually only succeeds with the more active bromo- or iodoaromatics. In the few described coupling reactions of metallates with chloro- or fluorobenzenes, it is often necessary to use large quantities of specially developed and usually very expensive ligands, so that this alternative is not usually given serious consideration.
A further significant disadvantage of the process mentioned concerns the apparatus. From the point of view of process engineering, preparing Grignard compounds from chloro- or fluoroaromatics is also problematic because the reaction frequently does not start at all at first only then to light off very suddenly and in an often uncontrolled fashion. It is often observed that the time until the start of the reaction depends very strongly on the quality of the solvent used (for example, water content, content of radical formers and metal ions, etc.). These are not ideal preconditions for a controlled industrial process.
However, the greatest problem and the biggest cost factor in the preparation of alkyl- and aryl-substituted aromatics from chloro- and fluorobenzenes is the considerable cost and effort associated with the apparatus. Since the resulting aryl metallates, for example the repeatedly mentioned aryl Grignard compounds, can only be obtained commercially in very few cases and then at horrendous cost, the Grignard compound has to be prepared in a first tank, which is usually held at reflux temperature, cooled therein after complete conversion, the appropriate carbon electrophile pre-charged to a second tank and, in view of the high reactivity of the aryl metallates, usually cooled to very low temperatures, then the similarly cooled Grignard compound metered in, thawed, hydrolyzed in a third tank (tanks 1 and 2 have to remain absolutely water-free) and the workup carried out in this third or a further tank. The simultaneous occupation of several tanks and the necessary lengthy heating and cooling phases of relatively large quantities results in only average space-time yields being achieved and high overall preparation costs.
The preparation of other organometallic reagents, e.g. based on the metals of zinc, aluminum, sodium, potassium or silicon, likewise does not present a sensible alternative, since the metals are usually too unreactive to react with chloroaromatics (Zn, Al, Si), or since the resulting metallates couple very easily to give biaryls and other products or tend to rearrange intramolecularly (K, Na, e.g. tolylsodium and tolylpotassium rearrange to give benzyl metallates).
It would therefore be very desirable to have a processxe2x80x94while retaining the raw materials chloro- or fluoroaromatics and carbon electrophilexe2x80x94which ideally involves all process steps being operated at one and the same temperature or at only slightly differing temperatures and thus avoiding long heating and cooling phases. Even more important would be the ability to carry out the preparation of the organometallic reagent in the same tank in which the reaction with the carbon electrophile is carried out. However, since the preparation of the Grignard compound usually has to be carried out at the reflux temperature of the solvent used but the addition of the reaction partner has to be carried out at temperatures of  less than 0xc2x0 C. for selectivity reasons, this does not appear to be possible via a Grignard route.
A further route which is frequently used for preparing alkyl- or aryl-substituted aromatics is the reaction of lithiated aromatics and heteroaromatics with carbon electrophiles. Lithioaromatics can likewise be prepared in numerous ways. For example, reaction of bromoaromatics and iodoaromatics with butyllithium is a standard method of generating lithioaromatics. This exchange can be carried out at low temperatures at which the reactions with carbon compounds can then be carried out with high selectivity.
However, this reaction can unfortunately not be carried out using chloroaromatics, since, with very few exceptions, these do not react with butyllithium. This fact and the high cost of butyllithium results in a process which is overall not particularly economical despite the advantages mentioned.
The prior art discloses various methods for preparing lithium compounds. However, no overall process for exchange of chlorine or fluorine with alkyl or aryl radicals which fulfills all of the requirements described above has hitherto been described.
It is an object of the present invention to provide a process for preparing compounds of the formula (I) which starts from easily available and convenient chlorine or fluorine compounds, and makes the required aryl- or alkyl-substituted aromatics and heteroaromatics accessible in good yields and high purities and is at the same time simple in process engineering terms, efficient and cost effective. The latter automatically implies the operation of all process steps with the exception of hydrolysis and workup at one and the same temperature and if possible in one and the same reaction vessel. Ideally, the process shall also make it possible to prepare the target compounds directly by simple stirring of chloroaromatic, metal and carbon electrophile in a suitable solvent.
The present invention achieves all these objects and provides a process for preparing compounds of the formula (II), 
where X6 to X9 and R6 to R9 have the same meaning as X1 to X5 and R1 to R5 and
the radical Caryl, alkyl is CH3, straight-chain or branched, substituted or unsubstituted C1-C8-alkyl, in particular C1-C4-alkyl, 1-hydroxyalkyl having from 1 to 8 carbon atoms, CN, 2-hydroxyalkyl having from 2 to 5 carbon atoms, 3-hydroxyalkyl having from 3 to 5 carbon atoms, 1-NHR-alkyl having from 1 to 5 carbon atoms, CH(OC1-C5-alkyl)2, C(C1-C5-alkyl)(OC1-C5-alkyl), CH2(OC1-C5-alkyl), CH(CH3)(OC1-C5-alkyl), C1-C5-alkoxy, in particular C1-C4-alkoxy, N(C1-C5-alkyl)2, phenyl, substituted phenyl, aryl, heteroaryl, CO2H, CO2alkyl, (Cxe2x95x90O)0.5, (which would correspond to the structural unit Arxe2x80x94COxe2x80x94COxe2x80x94Ar), substituted 1-vinylalkyls, CH3xe2x80x94C(xe2x95x90O), Rxe2x80x94C(xe2x95x90O) or CHO,
which comprises reacting chloro- or fluoroaromatics of the formula (I) with carbon electrophiles and lithium metal.
The carbon electrophile is in particular selected from one of the following categories:
aryl or alkyl cyanates (Caryl,alkylxe2x95x90CN)
oxirane, substituted oxiranes (Caryl,alkylxe2x95x90CH2CH2OH, CR2CR2OH) with Rxe2x95x90R1 (identical or different)
azomethines (Caryl,alkylxe2x95x90CR12xe2x80x94NRxe2x80x2H)
nitroenolates (Caryl,alkylxe2x95x90oximes)
immonium salts (Caryl,alkylxe2x95x90amines)
haloaromatics, aryl triflates, other arylsulfonates (Caryl,alkylxe2x95x90aryl, heteroaryl)
carbon dioxide (Caryl,alkylxe2x95x90COOH)
carbon monoxide (Caryl,alkylxe2x95x90(xe2x80x94COxe2x80x94)0.5)
aldehydes, ketones (Caryl,alkylxe2x95x90CHR1xe2x80x94OH, CR12xe2x80x94OH) xcex1,xcex2-unsaturated aldehydes/ketones (Caryl,alkylxe2x95x90CH(OH)-vinyl, CR1(OH)-vinyl)
ketenes (Caryl,alkylxe2x95x90C(xe2x95x90O)CH3 in ketene, C(xe2x95x90O)xe2x80x94R1 in substituted ketenes)
alkali metal and alkaline earth metal salts of carboxylic acids (Caryl,alkylxe2x95x90CHO in formates, COCH3 in acetates, R1CO in R1COOMet)
aliphatic nitriles (Caryl,alkylxe2x95x90COCH3 in acetonitrile, R1CO in R1CN)
aromatic nitriles (Caryl,alkylxe2x95x90COArxe2x80x2)
amides (Caryl,alkylxe2x95x90CHO in HCONR2, C(xe2x95x90O)R in RCONRxe2x80x22)
esters (Caryl,alkylxe2x95x90[C(OH)R1]0.5) or
alkylating agents (Caryl,alkylxe2x95x90alkyl).
The process of the invention provides a method for converting the inexpensive and easily accessible chloro- and fluoroaromatics as ideal starting molecules into a wide gamut of compounds while adding value.
A preferred embodiment is the simultaneous stirring of the carbon electrophile, chloro- or fluoroaromatic and lithium metal in a suitable solvent (one-pot variant), in which, after appropriate workup (usually hydrolysis), the resulting products are often obtained in good yields. As long as no functional groups are present in the reactants which react even faster with lithium metal, the method delivers very high space-time yields and additionally only requires a single tank. In some cases, space-time yields of up to 0.3 kg of product/(L*h) are achieved.
A further preferred embodiment is particularly advantageous when, for the above or other reasons, the one-pot variant cannot be employed, and involves the primary quantitative preparation of lithium compound and subsequent reaction with carbon electrophile. In a particularly preferred embodiment, both steps are carried out at the same or only slightly differing temperatures, which allows time-consuming and energy-intensive heating and cooling phases to be avoided.
Useful solvents for the carbonxe2x80x94carbon bond forming method of the invention are aliphatic and aromatic ethers and hydrocarbons and amines which do not carry a hydrogen on the nitrogen atom, preferably triethylamine, diethyl ether, tetrahydrofuran, toluene, toluene/THF mixtures, anisole and diisopropyl ether, more preferably toluene, THF or diisopropyl ether. Concentrations of solutions are preferably in the range from 1 to 60% by weight, in particular 5 to 40% by weight, more preferably 8 to 30% by weight.
The conversions of the invention are advantageously carried out at temperatures in the range from xe2x88x92100xc2x0 C. to +80xc2x0 C., preferably from xe2x88x9280xc2x0 C. to +20xc2x0 C., more preferably from xe2x88x9265xc2x0 C. to xe2x88x925xc2x0 C.
The lithium can be used in the present process in the form of a dispersion, a powder, turnings, sand, granules, pieces, bars or in another form, although the size of lithium particles is not qualitatively relevant, but merely influences the reaction times. For this reason, preference is given to relatively small particle sizes, for example granules, powder or dispersions. The added lithium quantity per mole of halogen to be converted is from 1.95 to 2.5 mol, preferably from 1.98 to 2.15 mol.
The workup is generally aqueous, and either water or aqueous mineral acids are metered in or the reaction mixture is metered into water or aqueous mineral acids. To achieve the best yields, the pH is set to that of the product to be isolated in each case, thus usually a slightly acidic, or in the case of N-heterocycles, slightly alkaline pH. The alkylated or arylated products are recovered, for example, by extraction and evaporation of the organic phases, or alternatively, the organic solvents may be distilled out of the hydrolysis mixture and the precipitated product recovered by filtration.
The purities of the products from the process of the invention are generally high, but for special applications (pharmaceutical precursors) a further purification step, for example by recrystallization with the use of small quantities of activated carbon, may be necessary. The yields of the reaction products are from 70 to 99%, typical yields are in particular from 85 to 95%.
The raw materials for the synthesis of the invention (chloroaromatics and fluoroaromatics) are generally commercially obtainable and very inexpensive, so that in combination with the stated process engineering advantages and associated high space-time yields and very high product purities, an extremley economical and very generally applicable process for carbonxe2x80x94carbon bond formation of the invention has been found.
The process of the invention is illustrated by the following nonlimiting examples: